Dependence potential of oripavine

Sections

ABSTRACT
Introduction
General pharmacology and toxicology of oripavine
Physical dependence on oripavine
Reinforcing effect of oripavine
Further metabolic studies on thebaine
Discussion and conclusion

Details

Pages: 29 to 35
Creation Date: 1981/01/01

Dependence potential of oripavine

Report of a WHO Advisory Group

ABSTRACT

The dependence potential of thebaine is at least partially attributed to oripavine which is one of the principal metabolites of thebaine. The analgesic potency of oripavine in mice is found to be much higher than that of thebaine and comparable to morphine. The reinforcing effect of this substance also appears to be more potent than thebaine. In rats the physical dependence potential of oripavine at a dose of 4 mg/kg is almost comparable to that of morphine at 0.5 mg/kg. Studies carried out on monkeys show that oripavine possesses weak morphine-antagonist properties. Further pharmacological studies of other metabolites of thebaine are recommended.

Introduction

This paper is based on the report of a WHO advisory group 1which met from 22 to 24 September 1980 at Geneva to review psychoactive substances for international control. The paper presents additional information to the study on thebaine published earlier in the Bulletin [ 1] .

New findings which have been made since then are outlined, particularly with respect to the dependence potential of oripavine, known as one of the major metabolites of thebaine in the rhesus monkey. This study has been supported by the United Nations Fund for Drug Abuse Control.

1. The members of the group were Dr. Pierre Chanoit, Institut Marcel Rivière, France; Dr. H. Halbach, Honorary Professor, University of Munich, Federal Republic of Germany; Dr. Louis S. Harris, Chairman, Medical College of Virginia. Virginia Commonwealth University. United States; Dr. D. Jasinski, Director, Addiction Research Center. National Institute on Drug Abuse. United States; Dr. J. Knoll. Head, Department of Pharmacology, University of Semmelweis. Hungary; Dr. V. Navaratnam, Director, National Drug Dependence Research Centre. Malaysia; Dr. O. O. Ogunremi, Professor and Head of the Department of Behavioural Sciences, University of llorin. Nigeria; Major General Doctor Muhammed Shuaib, Consultant Psychiatrist. Pakistan Army, Pakistan Narcotics Control Board. Pakistan; Dr. Charles Schuster, Department of Psychiatry, University of Chicago, United States; Dr. K. Setyonegoro, University of Indonesia, Directorate of Mental Health, Ministry of Health, Indonesia: Dr. T. Yanagita, Director, Preclinical Research Laboratories. Central Institute for Experimental Animals, Japan; representing the United Nations: Dr. George M. Ling, Director. Division of Narcotic Drugs, and Mr. P. K. Bailey, Division of Narcotic Drugs; representing the International Narcotics Control Board: Dr. T. L. Chrusciel, Deputy Director. Institute for Drugs. Research and Control, Poland; representing the International Criminal Police Organization: Mr. G. Atkinson, Drugs Sub-Division. The secretariat of the group consisted of Dr. Inayat Khan. Senior Medical Officer. Division of Mental Health, WHO (Secretary), and Dr. P. Kalix, Department of Pharmacology, School of Medicine, Geneva.

General pharmacology and toxicology of oripavine

Gross behavioural observation

Rat

The gross behavioural effects of intravenous single doses of oripavine were observed in normal rats. The minimal effective dose was 0.24 mg/kg; the spontaneous motor activities were lost immediately after administration. The maximal tolerable dose was 4 mg/kg, at which dose the animals showed pre-convulsive disorders such as hyperirritability, tremor, muscle rigidity, motor impairment and transient muscle contraction. These signs lasted more than one hour after administration but the rats survived. At 5 mg/kg, however, the rats died immediately after administration in a persistent tonic seizure [ 2] .

Rhesus monkey

Yanagita conducted a gross behavioural observation of the acute effects of oripavine in rhesus monkeys by subcutaneous administration of the drug at single doses of 0.06, 0.25, 1 and 4 mg/kg, using saline as the control agent under a blind procedure. The mininal effective dose was 1 mg/kg, and at this dose the monkeys manifested a decrease in spontaneous motor activity, occasional eye-closing, vomiting and tremor. These effects lasted for less than two hours. At 4 mg/kg, vomiting and tremor were exaggerated, and hyperirritability to sound stimuli, motor impairment and pre-convulsive disorders were observed for about 1.5 hours after administration [ 2] . Harris administered oripavine to a rhesus monkey at a cumulative subcutaneous dose of 5.6 mg/kg over 45 minutes (0.8, 1.6 and 3.2 mg/kg at 15-minute intervals) and observed severe tremors which were terminated with pentobarbital and morphine [ 3] .

Analgesic test in mice

The ED 50s for the analgesic effect of oripavine were assessed in mice by subcutaneous single dose administrations of the drug in the following tests: ( a) 3.03 mg/kg in the tail flick test; ( b) 1.7 mg/kg in the paraphenylquinone-induced writhing test; ( c) 1.5 mg/kg in the hot plate test [ 3] .

Morphine antagonism test in morphine-dependent monkeys

Oripavine was administered subcutaneously to morphine-dependent non-withdrawn monkeys at doses of 0.25 and 1.0 mg/kg. In contrast to the control animals which were non-dependent and received 1 mg/kg of oripavine, the dependent monkeys manifested more severe apprehension and tremors 15 to 20 minutes after oripavine administration [ 2] .

Physical dependence on oripavine

Substitution studies in morphine-dependent monkeys

Rhesus monkeys, made physically dependent by repeated administration of morphine, were withdrawn and then received single doses of oripavine subcutaneously (s.c.). Harris gave 0.5, 1 and 2 mg/kg of oripavine to two monkeys each, without observing any suppression of the morphine withdrawal signs [ 3] . Yanagita conducted the same experiment using 0.25 and 1 mg/kg of oripavine with the same result, but further observed a slight exaggeration of the withdrawal manifestation [ 2] .

Development of physical dependence on oripavine in rats

Oripavine, morphine, codeine, pethidine and pentazocine were administered hourly for three days through intravenous catheters using a timer-programmed drug-infusion apparatus. Withdrawal signs were then precipitated by naloxone at 4 mg/kg, s.c., and the severity of the signs was assessed by the number of points scored during one hour's observation. The scoring system is presented in table 1 [ 4] .

Table I

Scoring system for quantifying withdrawal signs in rats treated with morphine

Type

Signs

Conditions

Points

Behavioural signs
Unusual posture a
  2
 
Hyperirritability a
Touch
1
   
Approach
2
 
Teeth chattering a
Intermittent
0.5
   
Continuous
1
       
Autonomic signs
Lacrimation
  4
 
Diarrhoea
Soft
4
   
Unshaped
8
 
Salivation a
Slight
1
   
Marked
2
 
Body weight loss
<2%
0
   
<4%
5
   
<6%
10
   
<8%
15
   
= 8%
20
a

Scored every 15 minutes and cumulated for one-hour period in each rat.

b

Scored for one hour.

The results are summarized in the figure. Obvious morphine-like with- drawal signs were observed in the rats treated with oripavine, and the withdrawal severity at a unit dose of 4 mg/kg was comparable to that of morphine at 0.5 mg/kg, pentazocine at 4 mg/kg or pethidine at 8 mg/kg, but weaker than that of morphine at 2 mg/kg or codeine at 2 mg/kg [ 2] .

Reinforcing effect of oripavine

Cross self-administration of oripavine versus lefetamine in rhesus monkeys

Four monkeys were allowed to self-administer drugs intravenously for four hours daily. After testing for three days each with lefetamine and saline, oripavine was tested for a third 3-day segment at a unit dose of 15 μg/kg, after which the 9-day lefetamine-saline-oripavine test cycle was repeated for 4 μg/kg and 60 μg/kg. As a result, oripavine was found to be definitely reinforcing at unit doses of 15 and 60 μg/kg (see table 2) [ 2] .

Further metabolic studies on thebaine

In previous studies, several major metabolites of thebaine were found in the urine of rhesus monkeys treated with thebaine at single subcutaneous doses of 8 mg/kg, with two of the metabolites being identified by gas chromatographic-mass spectrographic analysis as oripavine (M 1) and nororipavine (M3) [ 1 ].

Recent in vitro studieson incubation of thebaine with rhesus monkeys' hepatic microsomes revealed that thebaine was metabolized mainly to oripavine, nororipavine and an unknown substance that was found by thin-layer chromatography to be identical with M2 and later identified by GC-mass spectrographic analysis as northebaine [ 5] .

Discussion and conclusion

In previous studies thebaine was found to possess a potential for both physical and psychological dependence which could be attributed to its meta-bolites. As oripavine is one of the major metabolites, its dependence potential was considered worthy of further investigation. The data since obtained which have been described above clearly indicate that:

  1. Oripavine is a pharmacologically active substance;

  2. Its analgesic potency assessed in mice is much higher than that of thebaine and comparable to that of morphine; in both tail flick and paraphenylquinone tests in which thebaine was reported to be inactive, the ED 50s of oripavine were respectively 3.03 and 1.7 mg/kg, s.c. (compared with morphine: 5.8 and 0.23 mg/kg, s.c., respectively);

Dependence potential of oripavine 33

Withdrawal signs precipitated in opiate-dependent rats. (Hourly intravenous infusion for three days, then precipitated by naloxone 4 mg/kg, s. c.)

Full size image: 44 kB, Withdrawal signs precipitated in opiate-dependent rats. (Hourly intravenous infusion for three days, then precipitated by naloxone 4 mg/kg, s. c.)

Table 2

Intravenous cross self-administration of oripavine with lefetamine and saline in rhesus monkeys

 

Percentage ratio of self-administration rate, lefetamine as 100 per cent

Oripavine

Monkey

Average self-administration rate 4 h/d, lefetamine 0.1 mg/kg injection

Saline 0.25 ml/kg injection

4 μg/kg injection

15 μg/kg injection

60 μg/kg injection

Female 5.8 kg
140.6 ± 16.7
8.0 12.6 28.7 18.7
Male 6.7 kg
104.0 ± 15.0
7.8 10.3 15.7 17.3
Male 6.2 kg
89.7 ± 16.8
17.7 36.8 17.8 41.6
Male 8.7 kg
260.0 ± 33.7
6.9 10.7 18.3 24.9
Mean ± S.D.
 
10.1 ±.5.1
17.6 ± 12.8
20.1±5.8
25.6± 11.2
t value against saline
    1.0861
2.5917 a
2.5332 a
a

p < 0.05.

  1. It possesses a weak morphine-antagonistic property as evidenced by its partial precipitation of morphine withdrawal signs in morphine-dependent non-withdrawn monkeys, and by its exaggeration of morphine withdrawal signs in morphine-dependent withdrawn monkeys;

  2. Its physical dependence potential as assessed by hourly intravenous administrations for three days at a submaximal, tolerable dose (4 mg/kg) to rats is almost comparable to that of morphine at 0.5 mg/kg, pethidine at 8 mg/kg or pentazocine at 4 mg/kg, but lower than morphine at 2 mg/kg and codeine at 2 mg/kg;

  3. Its reinforcing effect appears to be more potent than thebaine.

These results may also indicate that the onset of the pharmacological effects of oripavine is significantly faster than that of thebaine [6].

Contrary to the fact that development of physical dependence was observed in rats, the results of the substitution tests conducted in morphine dependent and withdrawn monkeys did not show suppression of the morphine withdrawal signs. However, it is known that the physical dependence potential of morphine antagonists or partial agonists may not be demonstrable because the antagonistic property of these drugs may prevent the suppression of morphine withdrawal signs [ 7] . Thus it may be concluded that the dependence potential of thebaine in both its physical and psychological aspects is at least partially attributable to oripavine, one of thebaine's major metabolites. Further pharmacological studies of other metabolites of thebaine, such as northebaine and nororipavine are recommended.

References

001

"The dependence potential of thebaine", Report of a WHO Advisory Group, Bulletin on Narcotics , vol. 32, No. 1 (1980). pp. 45-54.

002

T. Yanagita and others, unpublished data.

003

L.S. Harris and others, unpublished data.

004

T. Yanagita, K. Arimura and H. Kiyohara, "Development of physical dependence by short-term frequent infusion of analgesics in rats", Preclinical Report of Central Institute for Experimental Animals , vol. 5, No. 2 (1979), pp. 139-143.

005

Y. Yamazoe, H. Numata and T. Yanagita, "Thebaine metabolites in the urine of rhesus monkeys (part 2)", Japanese Journal of Pharmacology , vol. 31, 1981, pp. 433-442.

006

M. D. Aceto and others, "Dependence studies of new compounds in the rhesus monkey", in Proceedings: 39th Annual Scientific Meeting, Committee on Problems of Drug Dependence (Cambridge, Massachusetts, 1977), pp. 586-613.

007

T. Yanagita, "An experimental framework for evaluation of dependence liability of various types of drugs in monkeys", Bulletin on Narcotics , vol. 25, No. 2 (1973), pp. 57-64.